The study of cytokines is important to understanding inflammation and the immune system. Cytokines function to mediate normal physiologic processes, such as infection control and wound healing, but they can also regulate disease states such as autoimmune disease, rheumatoid arthritis (RA), or asthma. Interleukin (IL)-18 is a proinflammatory Cytokine, initially described as interferon-gamma- inducing factor. It is produced by activated macrophages, Kupffer cells, articular chondrocytes, osteoblasts, kerotinocytes, and synovial fibroblasts. IL-18 is structurally similar to IL-l beta and shares some of its biological actions, such as upregulation of the TH1 Cytokine and cell activation. Previous work has demonstrated its increased presence in RA and in an animal arthritis model. Preliminary evidence from our lab also supports a role for IL-18 in mediating angiogenesis, or new blood vessel growth, which is integral to the vasculoproliferation seen in RA as well as in would healing and tumorigenesis. IL-18 clearly contributes to the Cytokine cascade and maintains inflammation. However, the mechanisms by which IL-18 functions and its contributions to inflammatory disease processes need further investigation. The goal of the proposed research plan is to test our hypothesis that IL-18 contributes to the development of inflammation and angiogenesis in RA. The specific aims of the research are to determine: (I.) the cellular effects of IL-18 on stimulation of inflammatory mediators in RA synovial fibroblasts, which will be accomplished by determining whether IL-18 upregulates chemokines (chemotactic cytokines), arachidonic acid metabolites, degradative enzymes, and cell surface markers of inflammation; (II.) the action of IL-18 on an / inflammatory joint disease model, by employing mice deficient in the IL-18 gene, and examining the development of inflammation clinically and immunohistologically compared to normal mice; (III.) the angiogenic role of IL-18 in vitro and in vivo, by testing IL-18 in various bioassays for angiogenesis, including endothelial cell chemotaxis, proliferation, and tube formation, as well as blood vessel growth in vivo; (IV.) the action of IL-18 in mediating angiogenesis, employing in vivo angiogenesis and granuloma assays; (V.) the mechanisms by which IL-18 functions are regulated in a component of angiogenesis, namely endothelial cell migration. These research aims, if answered by the experimental methods above, will broaden our understanding of IL-18 functions and may ultimately direct the development of novel therapeutic targets against inflammatory and angiogenesis driven diseases.